Thiazide Dose, Urine Calcium, and Symptomatic Kidney Stone Events

This cohort study examines the association between thiazide dose and urine calcium reduction and correlates urine calcium changes with the occurrence of symptomatic kidney stone events.


Study population
We identified Medicare beneficiaries who had a 24-hour urine collection (Litholink, Labcorp, Itasca, IL) between January 1, 2011 and December 31, 2018.We used National Drug Codes (see eTable 1 below) to identify Medicare beneficiaries that had a prescription fill for a thiazide agent, specifically hydrochlorothiazide (HCTZ), chlorthalidone, or indapamide, within six months following their 24-hour urine collection.We identified the subset of beneficiaries who had a follow-up collection between 30 and 180 days after their first prescription fill of the thiazide agent.To allow for comorbidity adjustment and adequate follow up, we excluded beneficiaries without continuous enrollment in Medicare Parts A and B during the 1 year prior to the baseline 24-hour urine through 6 months after the initial prescription.To ensure capture of prescription coverage, we excluded beneficiaries without continuous enrollment in Medicare Part D during the 6 months prior to the baseline 24-hour urine through 4 months after the initial prescription to assess for adherence.We excluded those receiving thiazides or alkali citrate up to 6 months prior to the baseline 24-hour urine.We further excluded those receiving alkali citrate or allopurinol up to 120 days after thiazide initiation, those who changed daily dosing of thiazide between the baseline and follow-up urine collections, and those who had either inadequate baseline or follow-up 24-hour urine collections (normal 24-hour creatinine/kilogram body weight 11.9-24.4mg/kg males, 8.7 to 20.3 mg/kg females).See the cohort flow diagram in eFigure 1 below for more details.

Outcome assessment
To determine the urine calcium change, we calculated the difference between the urine calcium levels measured at the baseline 24-hour urine collection and the follow-up 24-hour urine collection.
To evaluate for symptomatic stone events, we identified the first occurrence of any stone-related emergency department visit, hospitalization, or surgery between six months and 4 years after the initial thiazide prescription.We identified emergency department visits by the presence of outpatient claims with revenue center codes 0450 to 0459 or 0981 or a non-zero emergency department charge amount in the MedPAR file (https://www.resdac.org/articles/how-identifyhospital-claims-emergency-room-visits-medicare-claims-data).We identified hospitalizations © 2024 Hsi RS et al.JAMA Network Open.
using claims in the MedPAR file and surgery from ICD procedure and CPT codes (see below for codes).We defined emergency department visits and hospitalizations as stone related if they had an associated primary diagnosis of kidney stone disease during the encounter (see below for codes).

Covariates
We assessed for the following covariates including age at first 24-hour urine test, sex, race/ethnicity, level of comorbid illness (number of hierarchical condition categories), region of residence, dual Medicare-Medicaid eligibility status, high-risk status for stone recurrence, medication adherence, and baseline urine calcium at first 24-hour urine test.Level of comorbid illness was measured using diagnoses from the year prior to the first 24-hour urine test (PMID: 15493448).Medication adherence was defined as >80% days covered from start of thiazide prescription fill to 6 months (PMID: 26485048).High-risk status was determined if there were diagnoses putting the patient at higher risk for kidney stones in the year prior to the first 24-hour urine test (PMID: 35182586, see eTable 2).

Statistical Analysis
We compared adjusted mean absolute and mean percent differences of urinary calcium for low, medium, and high thiazide daily doses.Doses were classified as low (chlorthalidone <12.5mg per day, indapamide <0.6125mg per day, HCTZ <25mg per day), medium (chlorthalidone 12.5mg to <25mg per day, indapamide 0.6125 to <1.25mg per day, HCTZ 25mg to <50mg per day), and high (chlorthalidone 25mg or higher, indapamide 1.25mg per day or higher, HCTZ 50mg per day or higher).We then evaluated changes in urine calcium based on the dosage prescribed, adjusting for age at first 24-hour urine test, sex, race/ethnicity, level of comorbid illness (number of hierarchical condition categories), region of residence, dual Medicare-Medicaid eligibility status, high-risk status for stone recurrence, medication adherence, and baseline urine calcium at first 24-hour urine test.For these comparisons, we used linear regression models.
To assess stone-related clinical events after thiazide initiation related to urine calcium changes, we categorized individuals from the entire cohort into terciles of urine calcium changes between the first and follow-up 24 hour urine test by absolute change.We used the Kaplan-Meier method    ICD-10 diagnosis M48.4xXA, M48.50XA, M80.08XA, M81.0, M81.8, M84.3xxx, M84.4xxx, M84.68XA, M85.x, M87.x, M89.x, M94.0, M94.20, M94,8X9, M94.9, S02.91XK, S02.92XK, S12.0xxx-S12.6xxx,S22.9XXK, S32.9XXK, S42.xxxx, S52.90xx, S62.90xx, S72.90xx, S82.00xx, S82.90xx, S92.90xx, S92.91xx, Z13.820, Z82.62, Z87.311 Patients aged 18 or older with a baseline 24-hr urine between 2011-2018 N= 141,544 Patients without continuous enrollment in Medicare Part D during 6 months before the baseline 24-hr urine up to 4 months after the initial receipt of PPT N= 828 Patients without a PPT fill for thiazides or alkali citrate within 6 months of the baseline 24-hr urine N= 104,744 Patients without continuous enrollment in Medicare Parts A and B during 1 year before the baseline 24-hr urine up to 6 months after the initial receipt of PPT N= 5,838 Patients with continuous enrollment in Medicare Parts A and B during 1 year before the baseline 24-hr urine up to 6 months after the initial receipt of PPT N= 13,950 Patients with a PPT fill within 6 months of the baseline 24-hr urine N= 36,800 Patients with receipt of prior alkali citrate or thiazides within 6 months before baseline 24-hr urine N= 17,012 Patients without receipt of alkali citrate or thiazides within 6 months before baseline 24-hr urine N= 19,788 Patients with continuous enrollment in Medicare Part D during 6 months before the baseline 24-hr urine up to 4 months after the initial receipt of PPT N= 13,122 Patients with a follow up 24-hr urine 30 to 180 days after initial receipt of PPT N= 2,919 Patients without a follow up 24-hr urine 30 to 180 days after initial receipt of PPT N= 7,845 Patients with both 24-hr urines meeting criteria for adequacy (Cr/Kg requirement within range, sex specific) N= 2,189 Patients without both 24-hr urines meeting criteria for adequacy (Cr/Kg requirement within range, sex specific National Drug Codes to Identify Prescription Fills for a Thiazide Agent Code eTable 1.
Algorithm for Identifying High-Risk Kidney Stone Patients © 2024 Hsi RS et al.JAMA Network Open.eTable 2.